(03) Biomarker Discovery and Validation general challenge Area and the 03-MH-101 Biomarkers in mental disorders specific challenge topic. Anorexia nervosa (AN) is a terrifying and perplexing disorder. Eating disorders, in general, rank among the top ten causes for disability among women, while AN has the highest mortality rate of any psychiatric disorder with a 57 fold increased risk of death due to suicide relative to an age- matched cohort. Despite these sobering statistics, one of the greatest mysteries of AN is that the ill state is prized by the individuals afflicted with this disorder. They report 'feeling better'while starved. In contrast, prior to the ill state, the majority with AN are diagnosed with an anxiety disorder and experience elevated levels of gastrointestinal symptoms, - conditions associated with increased visceral sensitivity. Notably, the severe starvation of AN principally onsets during adolescence, a vulnerable period of neural maturation and modification. Indeed, the course of AN is notable for a 'critical period'of intervention. The likelihood of improvement in symptoms of AN diminishes markedly if aggressive treatment is not undertaken during the vulnerable developmental window of early to middle adolescence. This body of evidence suggests that sensitivity to change in the internal state of the body (i.e. interoceptive sensitivity) exists premorbidly in those with AN, that biological alterations during adolescence may potentiate somatic sensitivity, that starvation during this period may dampen somatic experience, and that critical alterations in brain neural circuitry during this period may be crucial in shaping disorder course. In a sample of 75 adolescents (25 in the acute state of malnourishment of anorexia nervosa, 25 weight-restored from anorexia nervosa, and 25 typically developing controls), we will complete the following aims. We will: 1) characterize differences in interoceptive signaling from the upper GI tract and the interoceptive cortex, 2) characterize the differences in prefrontal cortical modulation of interoceptive cortex, and 3) characterize differences in the role of orbitofrontal cortex on modulation of cortical activity and connectivity with interoceptive cortex. By studying patterns of neural activation and psychophysical response that alter as a function of starvation and are associated with interoceptive sensitivity, we can formulate novel hypotheses on biological changes associated with starvation that are reinforcing for this group and derive novel treatment targets. PUBLIC HEALTH RELEVANCE STATEMENT: Anorexia nervosa (AN) is a terrifying and perplexing disorder. Eating disorders, in general, rank among the top ten causes for disability among women, while AN has the highest mortality rate of any psychiatric disorder with a 57 fold increased risk of death due to suicide relative to an age-matched cohort. Despite these sobering statistics, one of the greatest mysteries of AN is that the ill state is prized by the individuals afflicted with this disorder. They report 'feeling better'while starved. In contrast, prior to the ill state, the majority with AN are diagnosed with an anxiety disorder and experience elevated levels of gastrointestinal symptoms, - conditions associated with increased sensitivity to body changes (e.g. sensing the pit in your gut when you have done something wrong or the butterflies in your gut when you are worried about something). In fact, sensitivity to these internal sensations (called interoceptive sensitivity) has profound implications well beyond anorexia nervosa. Interoceptive sensitivity is associated with the strength of emotional memories, the depth with which we can understand others, and may be associated with the strength of emotional learning. As adolescence is a time of profound brain and body change, this developmental period may be a key window to study how individuals differ in this sensitivity and the boundaries that define pathological development. In fact, the severe starvation of AN principally begins during adolescence. Thus, malnourishment during this period may have particularly profound negative effects. In fact, the course of AN is notable for a 'critical period'of intervention. The likelihood of improvement in symptoms of AN diminishes markedly if aggressive treatment is not undertaken during the vulnerable developmental window of early to middle adolescence. Using functional neuroimaging we will examine neural circuits in the brain that may help us to identify brain regions that may contribute to difficulties with sensitivity to internal bodily states in those with anorexia nervosa and how these differ from typically developing adolescents. By studying patterns of neural activation and psychophysical response that alter as a function of starvation and are associated with interoceptive sensitivity, we can formulate novel hypotheses on biological changes associated with starvation that are reinforcing for this group and derive novel treatment targets for those with anorexia nervosa and better understand the transitioning mind-body connection of adolescence.